Evaluation, study, and treatment of patients with manic-depressive and schizo-affective illness are the primary goals of the Section. Double-blind, placebo-controlled clinical trials are employed to evaluate routinely used and novel agents for the treatment of these disorders. Anticonvulsants such as carbamazepine have been demonstrated to be clinically effective in the acute and prophylactic treatment of manic-depressive illness. We have identified possible clinical and biochemical markers of response to lithium versus carbamazepine and other agents. For example, antimanic responders to carbamazepine appear to be more severely ill, more dysphoric, and more rapidly cycling than non-responders, i.e., variables that tend to be associated with lithium nonresponse. In attempting to elucidate possible mechanisms of action, we have found that alpha-2 noradrenergic and "peripheral-type" benzodiazepine receptor mechanisms may be important to the anticonvulsant if not the psychotropic effects of carbamazepine. Other neurotransmitter, modulator, and peptide substances that may account for carbamazepine's positive effects on mood and behavior are being studied. The Section also seeks to identify regional alterations in brain electrophysiological and metabolic activity that are related to changes in behavior and cognition in affective illness. A clinical probe of limbic system excitability utilizing a novel provocative agent, procaine, is also being employed. Procaine selectively increases fast activity over the temporal lobe in association with a variety of behavioral and cognitive alterations and secretion of cortisol, ACTH, and prolactin. Animal models of electrophysiological and pharmacological kindling and cocaine-induced behavioral sensitization are studied and implicate conditioning and learning processes in the progressive behavioral changes induced. These models may help provide new clinical and biochemical insights into the mechanisms that underlie the progressive and long-term changes in behavior in a variety of clinical syndromes including cocaine-induced psychopathology and affective illness.